ES2390774A1 - A kit comprising a multi-chamber container - Google Patents

Abstract

The present invention refers to a kit comprising a multi-chamber container characterised in that the multi-chamber container comprises at least one chamber A and one chamber B, wherein the chamber A contains a pharmaceutically acceptable solution of at least one active ingredient and the chamber B contains a pharmaceutically acceptable solution for reconstitution of the solution contained in the chamber A. The invention provides a new kit for itraconazole for parenteral administration that consists of a double-chamber biocompatible plastic bag that comprises one chamber A containing a solution of itraconazole and one chamber B containing a pharmaceutically acceptable solution for the reconstitution of the itraconazole solution contained in the chamber A.

Description

FIELD OF THE INVENTION

The present invention relates to a kit comprising a multi-chamber container characterized in that the multi-chamber package comprises at least one chamber A and at least one chamber B, wherein chamber A contains a solution of at least one drug and the chamber B contains a pharmaceutically acceptable reconstitution solution of the chamber A solution.

BACKGROUND OF THE INVENTION

Many drugs useful in pharmacological applications are poorly soluble in water. In many cases, these drugs can be formulated as a suspension, in which case the lack of solubility of the drug in water does not usually have a negative impact on bioavailability. However, in situations where a solution of the drug is desired, the lack of solubility of the drug in water provides an important obstacle to obtaining the desired concentrations of the drug.

For example, the development of effective pharmaceutical compositions of azol-derived antifungals, such as, for example, itraconazole, fluconazole, voriconazole, posaconazole, clotrimazole, ketoconazole, clotrimazole, econazole, saperconazole, ravuconazole, isavuconazole, miconazole and thioconazole, is considerably impaired by the fact that such antifungals are poorly soluble in water.

The solubility and bioavailability of these poorly soluble drugs can be increased by complexation with cyclodextrins or their derivatives as described in EP0149197 and EP0335545.

Itraconazole is a broad-spectrum antifungal compound developed for oral, parenteral and topical use and is described for the first time in EP0006711.

5 1 O

ltraconazole is defined as (±) -1-sec-butyl-4- [p- [4- [p - [[(2R *, 4S *) - 2- (2,4-dichlorophenyl) -2- (1 H -1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] fenii] -Ll2-1, 2,4-triazolin-5-one, or, alternatively, as 4- [4- [4- [4 - [[2- (2,4-dichlorophenii) -2- (IH-1, 2,4-triazol-1-ylmethyl) -1, 3- dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropii) -3H-1, 2,4-triazol-3-one. There are three asymmetric carbons in itraconazole: one in the sec-butyl side chain of

triazolone and two in the dioxolane ring. As a result, there are eight possible stereoisomers of itraconazole: (R, R, R), (S, S, S), (R, R, S), (S, S, R), (R, S, S), (R, S, R), (S, R, S) and (R, S, R).

fifteen

The preferred compound of itraconazole is the (±) cis-itraconazole form comprising a 1: 1: 1: 1 mixture of the isomers (R, S, S), (R, S, R), (S, R, S ) and (S, R, R).

J

Jl -o-1 \ -o- ~ NN ~ dN ~! J N \ .__ / ~! J 0 '- (~~ --rf

ñ CI ~ CI

20 25

   (±) cis-itraconazole The term "itraconazole" as used hereinafter should be construed as (±) cis-itraconazole and comprises the free base form and pharmaceutically acceptable addition salts thereof. Itraconazole acid addition salts can be obtained by reacting the base form with an appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid,

2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, acid

propanedioic acid, butanedioic acid, (Z) -butene-dioic acid, (E) acid -

butenodioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid,

2-hydroxy-1, 2,3-propanotri-carboxylic acid, methanesulfonic acid, acid

5

ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, acid

cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2- acid

hydroxybenzoic and analogues.

Itraconazole is currently marketed under the name SPORANOX in

1O

oral capsule form, oral solution and concentrate for solution for

perfusion.

In particular, the SPORANOX parenteral administration kit containing

itraconazole includes (see the figure on page 16 of the technical data sheet of

fifteen

SPORANOX):

-A 75 ml flexible polypropylene infusion bag that houses a

50 ml volume of an injectable solution of 0.9% sodium chloride (in

weight / volume)

-A type 1 siliconized glass vial containing 25 ml of a

twenty

concentrated in water of 1 O mg / ml of itraconazole in the form of trihydrochloride,

salt formed in situ.

-An extension path formed by a polyvinyl chloride tube with a

two-way shut-off valve and an in-line filter.

The SPORANOX kit does not include the infusion path with drip chamber.

25

As indicated in section 6.6. of special precautions of

removal and other manipulations of the SPORANOX technical sheet, the

Itraconazole concentrate should be removed from the glass vial using a

needle of adequate length, not included in the SPORANOX kit, and

30

subsequently add the full volume of itraconazole concentrate to the

Perfusion bag by puncturing the port and gently mixing the

contents of the bag once the concentrate has been introduced

   completely. This infusion mixture should be used immediately; in

Otherwise, the storage time should not exceed 24 hours at a temperature of 2-8 ° C.

Next, the infusion mixture must be incorporated into the drip chamber infusion path, which is not included in the SPORANOX kit, and this in turn must be connected to the extension path with two-way shut-off valve and filter in line, yes included in the SPORANOX kit. Finally, the flow control device is opened until all the air has been expelled from the perfusion path and the extension path so that the infusion is already prepared for intravenous infusion to the patient. As indicated by the SPORANOX data sheet, the infusion stops when 60 ml equivalent to 200 mg of itraconazole have been administered.

The SPORANOX kit has different drawbacks, mainly due to the high handling required to prepare the infusion mixture before being administered to the patient together with the tendency of itraconazole to precipitate in water due to its low solubility. Although the kit was first authorized in Europe by the UK drug agency in 1996, it has not undergone any changes and the same kit is still being marketed without any significant variant.

On the one hand, the 1O mg / ml concentrate of SPORANOX itraconazole is a viscous solution of density 1.1 O -1.15 g / mi, so its complete removal of the glass vial by means of a syringe is an arduous task that inevitably implies material losses, a fact that translates into variations in the actual dose that is subsequently administered to the patient. In addition, the withdrawal of the concentrate through a syringe is not a sterile operation, so the risk of contamination during this stage is real, high and of great relevance for a product to be administered intravenously.

On the other hand, the introduction of SPORANOX concentrate by syringe into the infusion bag is a slow and tedious process, since it is necessary to avoid the incorporation of excess air that causes the formation of

foam in the diluted solution, hindering the homogenization process of

the solution and, therefore, delaying the administration. In addition the inventors

of the present invention have observed that during the introduction of

SPORANOX concentrate by syringe to the infusion bag is

5

produces visible turbulence due to the momentary precipitation of

Itraconazole that is subsequently redissolved. In fact the product

SPORANOX commercial pharmacist incorporates an online filter that we

clearly warns of the danger that itraconazole may precipitate in

any time or that really after reconstitution not all the

1O

Itraconazole remains completely dissolved. In addition the technical sheet of

SPORANOX indicates that itraconazole may precipitate when the

25 ml of concentrate in other types of infusion solutions other than

50 ml of 0.9% sodium chloride (by weight / volume), indicating the low

versatility of this pharmaceutical product in terms of choosing the

fifteen

reconstitution solution.

Another drawback of the SPORANOX kit is that of the 250 mg of itraconazole

which contains the concentrate only ends up giving the patient 200 mg,

which means that 50 mg of itraconazole, this is 20% of the total itraconazole,

twenty

They are directly discarded and, therefore, wasted. In section 2.2.

of dosage and method of administration of the SPORANOX data sheet

indicates that during the first two days of treatment two are performed

infusions / day and from the third day an infusion / day is performed. This

It implies a total of 16 infusions in the 14 days in which it is administered

25

at most SPORANOX, so that a total of 800 mg of

Itraconazole throughout the treatment.

Therefore, there is a need to offer alternative kits for drugs,

preferably for low water soluble drugs, such as

30

itraconazole, which must be reconstituted before parenteral administration

that do not involve so much manipulation in the preparation of the solution

reconstituted and that reduce the chances of contamination, avoiding,

   thus, all the inconveniences indicated above.

DESCRIPTION OF THE INVENTION

The present invention provides an alternative kit that allows mixing a

solution comprising a drug with a reconstitution solution of the

5

solution comprising the drug to obtain the reconstituted solution that

It must be administered to the patient.

The kit of the present invention allows to obtain the reconstituted solution for

parenteral administration more quickly, efficiently and without the

1 o

need to manipulate the solution comprising the drug. Therefore, it

eliminates the risk of contamination and ensures a constant dose at

patient.

On the other hand and surprisingly, the authors of the present invention have

fifteen

noted that in the kit of the present invention when the solution is mixed

comprising the drug, preferably a low water soluble drug,

and the solution for reconstitution of the solution comprising the drug, is

observe less precipitation of the drug than if the solution comprising the

drug is injected onto the solution of reconstitution of the solution of the

twenty

drug, which is the usual practice for the preparation of solutions

reconstituted that are administered parenterally. Therefore, the kit of the

present invention reduces the risk of drug precipitation,

preferably poorly soluble in water, in the reconstituted solutions that are

parenterally administered to the patient.

25

In a first aspect, the present invention provides a kit comprising

a multi-chamber container characterized in that the multi-chamber container

it comprises at least one camera A and at least one camera B, where the

chamber A contains a solution of at least one drug and chamber B

30

contains a pharmaceutically acceptable reconstitution solution of the

   camera solution A.

The multi-chamber package of the present invention comprises, for example, multi-chamber vials, multi-chamber ampoules, multi-chamber syringes, multi-chamber bottles and multi-chamber bags, preferably multi-chamber bags.

The multi-chamber package of the present invention may comprise from 2 to 5 cameras, preferably the multi-chamber container of the present invention comprises from 2 to 3 cameras, so that at least one camera contains a solution of at least one drug and at least one other chamber contains a pharmaceutically acceptable reconstitution solution of the drug solution.

The multi-chamber package of the present invention can have different configurations. For example, the chambers can be arranged adjacently or, alternatively, they can be embedded inside each other concentrically or non-concentrically.

In a preferred embodiment of the present invention the multi-chamber package is a package comprising a chamber A and a chamber B, wherein chamber A contains a solution of at least one drug and chamber B contains a pharmaceutically acceptable reconstitution solution of the solution of the chamber A, so that the package has the means so that the solution of the chamber A and the solution of the chamber B can be mixed within the same multi-chamber container by total or partial breakage of the separation between the camera A and camera B.

The chambers of the multi-chamber container of the present invention, especially when the multi-chamber package is a multi-chamber bag, can be separated from each other by a weld, that is to say by a welded separator zone, by a separation zone formed by any breakable plastic material or by a continuous closed line in which a break valve is inserted.

Alternatively the multi-chamber container of the present invention is a

package comprising a chamber A containing a solution of at least

a drug, a chamber B that contains a reconstitution solution

pharmaceutically acceptable solution of chamber A and chamber e

5

which is an empty chamber where the mixing of optionally can occur

the solution contained in chamber A with the solution contained in chamber B.

Optionally, the multi-chamber container of the present invention also

comprises a container comprising a chamber A containing a

solution of at least one drug, a chamber B that contains a solution of

1O

at least one drug and an e-chamber containing a solution of

pharmaceutically acceptable reconstitution of chamber solutions

Ay B.

In another preferred embodiment of the present invention the multi-chamber container

fifteen

It is a bio-compatible plastic multi-chamber bag. Preferably the bag

Bio-compatible plastic multi-chamber of the present invention is a bag

Dual chamber bio-compatible plastic.

Chamber A and chamber B of the bio-compatible plastic multi-chamber bag

twenty

of the present invention may be separated from each other by a weld,

that is to say by a welded separator zone, by a separation zone

formed by any breakable plastic material or a continuous line of

closed in which a break valve is inserted. Preferably the camera

A and chamber B of the bio-compatible plastic multi-chamber bag of the

25

The present invention are separated from each other by a weld.

The solder that separates chamber A and chamber B from the multi-chamber bag

Bio-compatible plastic of the present invention is constituted

preferably by a single welding line that can be oblique or

30

preferably vertical. Optionally the welding that separates chamber A and

the B-chamber of the bio-compatible plastic multi-chamber bag of the present

   invention may consist of more than one welding line,

preferably by two welding lines that can be in the form of L or

V-shaped.

Preferably chamber A and chamber B of the multi-chamber bag of

5

bio-compatible plastic of the present invention are each communicated

of them with the outside by a port where each one can be introduced

of the solutions contained in each chamber A and B, and then extract

the solution resulting from the mixture of the two solutions contained

initially in each of cameras A and B. Alternatively the bag

1O

Bio-compatible plastic multi-chamber of the present invention may include

also a third port through which to extract the solution resulting from the mixture

of the two solutions initially contained in chamber A and chamber

B.

fifteen

Figure 1 shows a particular and preferred embodiment of a multi-bag

Bio-compatible plastic chamber of the present invention:

(1) Camera A.

(2) Camera B.

(3) Vertical welding line.

twenty

(4), (5) Outside ports.

Prior to parenteral administration to the patient, the solutions

contained in chamber A and chamber B of the multi-chamber bag of

Bio-compatible plastic of the present invention is mixed by total breakage or

25

part of the weld that initially separates the two chambers A and B. This

Breaking occurs preferably by slight manual pressure on the

less one of the two chambers A or B. More preferably the breakage is

produces folding the bag perpendicular to the separation between

two chambers A and B and exerting manual pressure on the two chambers A and B.

30

Optionally it is also possible to provide the outer wall of the area of

separation of the two chambers A and B from a breakage tab,

   preferably with two break tabs.

Chamber A and chamber B of the bio-compatible plastic multi-chamber bag of the present invention may have the same volume or be of different volumes, preferably chamber A and chamber B have different volumes. The volumes of each chamber A and B may be between about 5 mL to about 200 mL, preferably between about 1 mL to about 100 mL, more preferably between about 20 mL to about 60 mL. Even more preferably chamber A has a volume of approximately 25 ml and chamber B has a volume of approximately 50 ml.

The bio-compatible plastic multi-chamber bag of the present invention is formed of a polymeric material that preferably is presented in the form of multilayer sheets. In a preferred embodiment, the multilayers consist of a film formed by two or seven layers, although a mono-sheet is possible as a polymeric material of the bio-compatible plastic multi-chamber bags of the present invention. The polymeric materials of the multilayer sheet must be chosen so as to ensure a weld, on the one hand, effective in separating the solutions contained in each of the two chambers A and B and, on the other hand, of easy breakage in order to mix The two solutions at the right time.

Non-limiting examples of the polymeric materials that may constitute the bio-compatible plastic multi-chamber bag of the present invention are polyolefins, cyclic polyolefins, polyesters and polyamides, preferably polyolefins. These polymeric materials can be used only, or two or more kinds can be mixed and used.

The polyolefins used preferably comprise homopolyethylene, polyethylene olefin copolymer, polypropylene homopolymer, polypropylene olefin copolymer, etc.

The polymeric materials that constitute the bio-compatible plastic multi-chamber bag of the present invention may, optionally, contain a material that has a gas barrier effect (such as oxygen, carbon dioxide or water vapor) avoiding the diffusion of these gases both inside and outside the bag. Non-limiting examples of materials having a gas barrier effect are polyvinyl alcohol (PVA), ethylene-vinyl alcohol copolymer (EVOH), polyvinyl acetate (PVAC), ethylene-vinyl acetate (EVA) copolymer, chloride Polyvinylidene (PVDC), polyglycolic acid, ethyl cellulose, cellulose acetate, nitrocellulose, high density polyethylene (HDPE), medium density polyethylene (MDPE), nylon, polystyrene (PS), polycarbonate (PC), polyacrylonitril, etc.

The polymeric materials that constitute the bio-compatible plastic multi-chamber bag of the present invention may, optionally, contain a material that has a light barrier effect, useful in the case where at least one lodged drug is photosensitive, such as itraconazole. Preferably to prevent diffusion of gases and / or to protect the drug or drugs housed from light, the bio-compatible plastic multi-chamber bag of the present invention is inserted into a blister.

The blisters that cover the bio-compatible plastic multi-chamber bag of the present invention are preferably plastic bags comprising one or more layers, preferably 2 or 3 layers. Non-limiting examples of plastics forming the blister used in the present invention are polyester, polypropylene and polyethylene. Preferably the blister used in the present invention is a double layer polyester / polyethylene film or a triple layer polyester / polypropylene / polyethylene film.

The thickness of the plastic that constitutes the blister is directly related to the effectiveness in preventing the diffusion of gases. The blister used in the present invention has a thickness between about 40 IJm to about 150 IJm, preferably between about 80 IJm to about 125 IJm, even more preferably about 112 IJm.

Optionally the blister used in the present invention can be a metallized blister to protect the drug or sheltered drugs from the action of light.

5 1O

In a preferred embodiment of the present invention, the solution in chamber A contains a solution, preferably aqueous, of at least one water-soluble drug, preferably an antifungal where the antifungal is an azol derivative, more preferably itraconazole, fluconazole, voriconazole, posaconazole, clotrimazole, ketoconazole, clotrimazole, econazole, saperconazole, ravuconazole, isavuconazole, miconazole or thioconazole, even more preferably itraconazole.

fifteen

In a preferred preferably aqueous embodiment, preferably itraconazole. of the camera present invention, the A comprises a single solution drug

twenty

In another preferred embodiment of the present invention, the solution in chamber A is an aqueous solution of the azol derivative, preferably itraconazole, of a concentration between about 1 mg / ml to about 30 mg / ml, preferably between about 5 mg / ml to about 20 mg / ml More preferably, the solution in chamber A is an aqueous solution of itraconazole with a concentration of approximately 10 mg / ml.

25 30

The aqueous solution of the azol derivative, preferably itraconazole, of the present invention has a volume between about 5 mi to about 100 mi, preferably between about 1 O mi to about 50 mi, more preferably between about 20 mi to about 25 mi, even more preferably about 25 ml.

   In another preferred embodiment of the present invention the solution of chamber A comprises at least one inclusion complex of the azol derivative -

cyclodextrin, preferably itraconazole -cyclodextrin. Examples no

Cyclodextrin limiting of the present invention are a, ~ or y-cyclodextrins

optionally substituted by hydroxyethyl, hydroxypropyl, dihydroxypropyl groups,

methyl hydroxyethyl, methyl hydroxypropyl, ethyl hydroxyethyl, ethyl hiproxypropyl, glucosyl,

5

maltosyl, maltotriosyl or sulfoalkyl ether, such as sulfobutyl ether.

Preferably the cyclodextrin used in the present invention is the

hydroxypropyl- ~ -cyclodextrin.

The weight ratio of cyclodextrin to weight of azol derivative,

1O

preferably itraconazole, in the solution of chamber A of the present

invention is between about 1: 1 to about 100: 1,

preferably between about 20: 1 to 50: 1, more preferably

of about 40: 1. In a preferred embodiment the derivative solution

of azol, preferably itraconazole, has a weight ratio of

fifteen

hydroxypropyl- ~ -cyclodextrin based on weight of azol derivative,

preferably itraconazole, about 40: 1.

In another preferred embodiment of the present invention the chamber solution

A further comprises a polymeric solubilizing agent or a mixture of

twenty

they. Non-limiting examples of polymeric solubilizing agents of the

present invention are polyethylene-propylene glycol copolymers, copolymers

polyoxyethylene-polyoxypropylene (poloxamer 188, poloxamer 407, poloxamer

124 or poloxamer 184) or copolymers of hydroxy (polyoxyethylene) -polyoxypropylene-

polyoxyethylene Preferably the polymeric solubilizing agent used in the

25

The present invention is a polyoxyethylene-polyoxypropylene copolymer and more

preferably it is poloxamer 188.

Optionally the solution of chamber A of the present invention can

simultaneously contain an azol derivative inclusion complex -

30

cyclodextrin, preferably itraconazole -cyclodextrin, and also an agent

   polymeric solubilizer or a mixture thereof.

In another preferred embodiment of the present invention, the solution in chamber A further comprises one or more solvents, and preferably the solvents are selected from the group of ethanol, propylene glycol, oils or glycerin, more preferably propylene glycol.

In another preferred embodiment of the present invention, the solution in chamber A further comprises one or more pharmaceutically acceptable acids, so that the low water soluble drug, preferably an antifungal where the antifungal is an azol derivative, more preferably itraconazole, is in the form of salt. Pharmaceutically acceptable acids comprise, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -butene-dioic acid, (E) -butenodioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1, 2,3-propanotri-carboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2- hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like, preferably hydrochloric acid.

In a preferred embodiment of the present invention, the solution in chamber A is an aqueous solution comprising an inclusion complex of itraconazole -hydroxypropyl- ~ -cyclodextrin, propylene glycol and hydrochloric acid, so that itraconazole is preferably in the form of salt , preferably in the form of trihydrochloride.

The solution of chamber B of the present invention comprises a solution for reconstitution of the solution of chamber A. A solution for reconstitution of the solution of chamber A is that solution that has the necessary components that causes the content to be combined once of chambers A and B, the resulting solution can be used directly for the desired purpose, such as being infused intravenously.

Non-limiting examples of reconstitution solution contained in chamber B

they are a solution of NaCI, a glucose solution, a dextrose solution or

a mixture thereof, preferably a solution of approximately NaCl

at 0.9% (by weight / volume).

5

The solution of chamber B of the present invention has a volume between

about 1 O mi to about 200 mi, preferably between

about 25 mi to about 100 mi, more preferably

between about 40 mi to about 50 mi. Even more

1 o

preferably the solution of chamber B of the present invention has a

volume of approximately 50 mi.

In a second aspect, the present invention provides a kit that

It comprises a bio-compatible plastic double chamber bag that

fifteen

it comprises a camera A and a camera B, characterized in that the camera A

contains between about 20 mi to about 25 mi of a

aqueous itraconazole solution of a concentration of approximately 1 O

mg / ml and, preferably also hydroxypropyl- ~ -cyclodextrin, propylene glycol and

hydrochloric acid, and chamber B contains between approximately 40 ml until

twenty

approximately 50 ml of a NaCI solution approximately 0.9%

(in weight / volume).

In a preferred embodiment of the present invention chamber A contains

approximately 25 ml of an aqueous solution of itraconazole of

25

concentration approximately 1 O mg / ml and, preferably also

hydroxypropyl- ~ -cyclodextrin, propylene glycol and hydrochloric acid, and chamber B

it contains approximately 50 ml of a solution of NaCI approximately

at 0.9% (by weight / volume).

30

In another preferred embodiment the kit of the present invention further comprises

a blister, preferably metallized, covering the multi-chamber container and,

optionally, an extension path formed by a plastic tube with a

   two-way shut-off valve and an in-line filter.

The kit of the present invention can be used as a medicament.

5

Preferably the pharmaceutical kit of the present invention comprising an antifungal, wherein the antifungal is an azol derivative, preferably itraconazole, can be used in the treatment of histoplasmosi, aspergillosis, candidiasis and cryptococcosis.

1O 15 20

The process for preparing kit of the present invention comprises, for example, the following steps: 1) Preparation of the drug solution. 2) Preparation of the pharmaceutically acceptable reconstitution solution of the drug solution. 3) Filtration of the drug solution and semi-automatic dosing in chamber A of the multi-chamber container of the present invention. 4) Filtration of the pharmaceutically acceptable reconstitution solution of the drug solution and semi-automatic dosing in chamber B of the multi-chamber container of the present invention. 5) Sterilization of the kit obtained in step 4). 6) Optionally, introduction of the kit obtained in step 5) in a blister pack. Step 1 and the filtration step of step 3 are preferably carried out in the presence of an inert atmosphere, for example, nitrogen or argon, preferably nitrogen.

25

Stages 2, 4 and the dosage step of step 3 preferably without the presence of an inert atmosphere. be They carry to cape

30

   The sterilization step 5 of the kit obtained after dosing the corresponding solutions in chambers A and B is preferably carried out by steam sterilization by heating in an autoclave, so that an F0 ~ 15 is achieved. According to the European Pharmacopoeia, The Fose parameter refers to the lethality equivalent in minutes at a temperature of 121 ° C. Preferably the kit obtained after dosing the corresponding ones

Solutions in chambers A and B are sterilized in an autoclave at a temperature of 121 ° C for 15 minutes, although alternatively other temperature and time conditions such as 116 ° C for 50 minutes can also be used.

Optionally and, preferably when at least one drug is photosensitive, as is the case with itraconazole, the solution containing said drug protected from light is maintained throughout the process indicated above.

Optionally, the kit obtained after the sterilization stage is covered with a blister which, preferably when at least one drug is photosensitive, as in the case of itraconazole, is a metallized blister (step 6).

The kit of the present invention comprising itraconazole has several advantages over the SPORANOX kit.

On the one hand, the kit comprising itraconazole of the present invention does not require any manual manipulation step of the itraconazole solution which is very viscous at the preferred concentration of the present invention of approximately 1O m g / mi. The SPORANOX kit involves two stages of manual handling of the itraconazole concentrate for the preparation of the solution that should be administered parenterally to the patient: extraction of the vial of itraconazole concentrate and its subsequent introduction to the infusion bag. With the kit of the present invention, these two stages are eliminated, so that the solution to be administered to the patient is obtained in a faster and more efficient way and, at the same time, the risk of contamination and loss of active substance is eliminated. thus ensuring a constant dose to the patient.

The inventors of the present invention have determined that manual extraction by syringe of the concentrate contained in the vial of the SPORANOX kit implies a loss of approximately 3% of the initial concentrate. In addition, it should be taken into account that the losses that occur can vary, and may even be greater, depending on the expertise with which this operation is performed. Therefore, with the SPORANOX kit, a constant dose is not guaranteed to the patient.

Since practically no material losses occur, except for the inevitable losses that occur throughout the perfusion line, the kit comprising itraconazole of the present invention allows to better adjust the amount of itraconazole to be administered to the patient; This is 200 mg, without the need to waste 20% of itraconazole that is wasted with the SPORANOX kit. This may involve saving up to 800 mg of itraconazole during the 14-day treatment with itraconazole.

In addition and, surprisingly, the kit comprising itraconazole of the present invention shows at least the same stability as the type 1 siliconized glass vial containing the itraconazole concentrate in the SPORANOX kit. The inventors of the present invention have found that the stability of an itraconazole solution of the same qualitative and quantitative composition as the itraconazole concentrate of the SPORANOX kit contained in chamber A of the multi-chamber bag, preferably double chamber, of plastic Bio-compatible of the present invention is at least equal to that of the itraconazole concentrate contained in the type 1 siliconized glass vial of the SPORANOX kit although the semi-automatic filling of the itraconazole solution in the chamber A of the multi-bag chamber, preferably double chamber, of bio-compatible plastic of the present invention is made without the presence of an inert atmosphere. Therefore, and using a more economical process, which does not require the use of nitrogen or argon, a solution of itraconazole of at least the same stability as the itraconazole concentrate of the SPORANOX kit is achieved.

In addition, according to the guidelines of the European Medicines Agency regarding the stability of new substances and products (see CPMP / ICH / 2736/99, August 2003), the stability tests to which a pharmaceutical product is subjected It depends on the container. For example, for waterproof containers, such as glass, the sensitivity of the solution to external moisture or a potential loss of solvent is not relevant, so stability tests can be carried out in any controlled condition of humidity or ambient humidity. In contrast, in the case of aqueous solutions packaged in semi-permeable containers, such as bags of a polyolefin bag, the potential loss of solvents as well as physical, chemical, biological and microbiological stability have to be evaluated. In addition, these tests must be carried out under very specific conditions. In other words, what the guidelines of the European Medicines Agency indicate, is that the stability of the itraconazole solution contained in chamber A of the multi-chamber bag, preferably double chamber, of bio-compatible plastic of the present In this case, it is inferior to the stability of the same itraconazole solution contained in a glass vial, taking into account that chemical inertia is not always satisfactory when liquid medicines are contacted with semi-permeable containers such as plastic (see Treaty of Farmacia Galénica, Luzán 5, SA of Ediciones, 1993, Chapter IV Stability of the medicine page 57 to 76).

In addition, the inventors of the present invention have found that, surprisingly, there is no alteration in the multi-chamber bag, preferably double chamber, of bio-compatible plastic comprising a solution of itraconazole in chamber A, even after the sterilization stage by autoclaving at high temperatures, such as at 131 ° C. Surprisingly, both the solutions and the packaging are stable after that treatment. For example, no hardening of the welding line that separates chambers A and B has been observed that would entail greater difficulty or even the impossibility of breaking said welding line to proceed to mixing the solutions contained in each of the A and B cameras.

The authors of the present invention have observed that during the addition of

itraconazole concentrate from the SPORANOX kit to the infusion bag that

Contains 0.9% sodium chloride solution (by weight / volume) is produced

a turbulence that does not disappear until the bag is slightly shaken

5

infusion for a minimum of two minutes. This momentary precipitation

of itraconazole in the SPORANOX kit is produced as it comes into contact

The two solutions break the balance between itraconazole and hydroxypropyl- ~

cyclodextrin established in the concentrate. In this way, the new system

you need a certain time for a new one to be reset

1O

balance between itraconazole and hydroxypropyl- ~ -cyclodextrin and thus obtain from

Again a visually transparent solution.

The authors of the present invention have observed that, surprisingly,

when mixing the itraconazole solution from chamber A with

fifteen

the NaCI reconstitution solution at approximately 0.9% (in

weight / volume) of chamber B of the kit of the present invention is only observed

a slight turbulence that disappears within a few seconds without the need

of shaking the bag manually. In principle the subject matter expert would have

expected that in the kit of the present invention itraconazole precipitation

twenty

be more abundant, since the two solutions are brought into contact

more sudden and less sequential than in the SPORANOX kit, where the

concentrate is injected with a syringe into the infusion bag by the

port puncture and, therefore, giving the system more time to allow

restore the balance between itraconazole and hydroxypropyl- ~ -cyclodextrin and

25

Resolution occurs. Therefore the kit comprising itraconazole of the

The present invention minimizes the risk of precipitation of itraconazole in the

reconstituted solution to be administered to the patient.

When the risk of precipitation of itraconazole is reduced, the risk of clogging

30

of the in-line filter that can be optionally added in the kit also

   minimizes

The term "kit" as used in the present invention refers to a

set of products and utensils enough to get a certain

In the end, they can be marketed as a unit. The present kit

invention comprises the multi-chamber package containing at least one

5

chamber A containing at least one solution of a drug and at least one

chamber B containing a pharmaceutically reconstitution solution

acceptable solution of chamber A, as well as said multi-chamber container,

optionally covered by a blister, preferably metallized,

together with other necessary utensils in parenteral administration

1 o

of drugs In a preferred embodiment of the present invention the kit

It consists of a multi-chamber container comprising at least one chamber A

which contains at least one solution of a drug and comprises at least one

chamber B containing a pharmaceutically reconstitution solution

Acceptable chamber solution A.

fifteen

Although the term "drug" in the present invention encompasses both the drug

in the form of free base as in the form of its addition salts

pharmaceutically acceptable, the term "little water soluble drug"

as used in the present invention refers to the drug in

twenty

Free base form preferably requires for its solution in water more than

1 000 parts of water per 1 part of drug, more preferably more

of 10,000 parts of water per 1 part of drug.

The term "concentrate" is used in the present invention to refer to the

25

itraconazole solution concentration around 1 O mg / ml kit

SPORANOX

The term "bio-compatible plastic" is used in the present invention to

refer to any plastic that in contact with the solutions herein

30

invention does not release any type of waste or if it does release some

type of waste, these are non-toxic and therefore compatible with a

   parenteral administration

The term "polymeric solubilizing agent" is used in the present invention to refer to any polymer that contributes to solubilize a drug in water.

5 1O

The term "in the presence of an inert atmosphere" as used in the present invention refers to maintaining the pharmaceutically acceptable drug and / or reconstitution solutions of the drug solution under an atmosphere consisting basically of an inert gas, for example nitrogen or argon and / or bubbling the pharmaceutically acceptable drug and / or reconstitution solutions of the drug solution with an inert gas, for example nitrogen or argon.

BRIEF DESCRIPTION OF THE FIGURE

fifteen

FIG. 1 shows an embodiment of a bio-compatible plastic multi-chamber bag.

twenty

EXAMPLES The present invention is further illustrated by examples that do not limit the scope of the invention in any way. following

EXAMPLE 1: It will be prepared below:

a solution from itraconazole with the formula indicated to

ITRACONAZOL

10 mg

HIDOXIPROPIL- ~ -CICLODEXTRINE

400.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

INJECTABLE WATER

c.s.p. 1 mi

The hydroxypropyl- ~ -cyclodextrin was stirred until complete with water for injections. To the resulting solution was added propylene glycol, the acid

hydrochloric and itraconazole. Stirring was maintained until a solution. The pH solution was adjusted to pH 4.5 by the addition of NaOH and finally flush to desired volume with water to injectable This resulted in a colorless transparent solution (or slightly yellow) and free of particles.

Preparation of a 0.9% NaCI solution (by weight / volume) A solution of NaCI was prepared with the formula indicated below:

I was born

9mg

HCI or NaOH 0.5 N

c.s.p. pH 4.5-6.5

INJECTABLE WATER

c.s.p. 1 mi

10 The NaCl was stirred until completely dissolved with water for injections. The pH was adjusted to 5, 1. It was finally flush to desired volume with water for injections.

Filling of the double chamber bag (chamber A and chamber B) of polyolefin 15 The two solutions prepared in the previous sections were filtered separately by vacuum pump with 0.22 IJm filters.

In the semi-automatic bag dosing machine, 25 ml of the itraconazole solution of 1 Omg / ml were dosed first in chamber A of

20 25 ml of volume and chamber A was closed with the help of the port and then 50 ml of the 0.9% NaCI solution (by weight / volume) in chamber B of 50 ml of volume, with the subsequent closed.

The double chamber bag was subsequently sterilized in the autoclave

25 being subjected to 121 ° C for 15 m in, achieving a sterile product for injectable use.

The double chamber bag was coated with a metallized polyester / polyethylene blister of 112 IJm thickness.

EXAMPLE 2:

As described in example 1, double chamber bags were prepared

(chamber A and chamber B) of polyoelefin:

- dosing 20 ml of the solution of itraconazole of 1 O mg / ml in chamber A and

5

40 ml of 0.9% NaCI solution (by weight / volume) in chamber B.

- dosing 21 ml of the 10 mg / ml itraconazole solution in chamber A and

42 ml of 0.9% NaCI solution (by weight / volume) in chamber B.

- dosing 22 ml of the 1 O mg / ml itraconazole solution in chamber A and

44 ml of 0.9% NaCI solution (by weight / volume) in chamber B.

1O

- dosing 23 ml of the itraconazole solution of 1 O mg / ml in chamber A and

46 ml of 0.9% NaCI solution (by weight / volume) in chamber B.

- dosing 24 ml of the itraconazole solution of 1 O mg / ml in chamber A and

48 ml of 0.9% NaCI solution in chamber B.

fifteen

EXAMPLE 3:

Be

will prepare a solution from itraconazole with the formula indicated to

continuation:

ITRACONAZOL

10 mg

HIDOXIPROPIL- ~ -CICLODEXTRINE

400.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

INJECTABLE WATER

c.s.p. 1 mi

On water for injections, hydrochloric acid and propylene glycol were incorporated.

In addition, a solid dispersion of hydroxypropyl- ~ -cyclodextrin and the

Itraconazole by successive dilution technique. Once the

homogeneity of the solid dispersion obtained, was added on the solution of hydrochloric acid and propylene glycol and stirring was maintained until solution

total. The pH of the solution was adjusted with a sodium hydroxide solution.

until pH 4.5 approximately and finally the solution was made up to desired volume with water for injections. In this way, a colorless (or slightly yellow) clear solution free of particles was obtained.

EXAMPLE 4:

5 A solution of itraconazole will be prepared with the formula indicated below:

ITRACONAZOL

10.00 mg

HIDOXIPROPIL- ~ -CICLODEXTRINE

200.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

INJECTABLE WATER

c.s.p. 1 mi

Be

waved in Water for injectable he itraconazole, the hydroxypropyl- ~

cyclodextrin,

he propylene glycol and the hydrochloric acid. A time obtained a

1O

homogeneous solution of the active substance, the pH at approximately

4.5 with a solution of sodium hydroxide and finally the solution was flush

up to desired volume with water for injections .. It was obtained in this way

a

solution transparent colorless (or slightly yellow) Y free from

particles

fifteen

EXAMPLE 5:

Such

Y how be describe in he example 4 be will prepare a solution from

itraconazole with the formula indicated below:

ITRACONAZOL

10.00 mg

HIDOXIPROPIL- ~ -CICLODEXTRINE

300.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

   INJECTABLE WATER

c.s.p. 1 mi

EXAMPLE 6: A solution of itraconazole with the formula indicated at continuation:

ITRACONAZOL

10.00 mg

POLOXAMER 188

60.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

INJECTABLE WATER

c.s.p. 1 mi

5 Itraconazole, poloxamer, propylene glycol and hydrochloric acid were stirred in water for injections. Once a homogeneous solution of the active ingredient was obtained, the pH was adjusted to approximately 4.5 with a solution of sodium hydroxide and finally flush to desired volume with water for injections. A colorless transparent solution was thus obtained.

10 (or slightly yellow) and free of particles.

EXAMPLE 7:

As described in example 3, a solution of

itraconazole with the formula indicated below:

ITRACONAZOL

8mg

HIDOXIPROPIL- ~ -CICLODEXTRINE

400.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

INJECTABLE WATER

c.s.p. 1 mi

EXAMPLE 8: As described in example 3, a solution of itraconazole will be prepared with the formula indicated below:

ITRACONAZOL

12 mg

HIDOXIPROPIL- ~ -CICLODEXTRINE

400.00 mg

PROPYLENE GLYCOL

25.95 mg

HCI 37% by weight

12.12 mg

NaOH

c.s.p. pH 4.00-5.00

INJECTABLE WATER

c.s.p. 1 mi

EXAMPLE 9 As described in examples 1 and 2, the solutions prepared in examples 3-8 were used to fill one of the bag chambers

5 double chamber (chamber A and chamber B) of polyolefin of the present invention.

Claims (12)

1. Kit comprising a multi-chamber container characterized in that the multi-chamber package comprises at least one chamber A and at least one 5 chamber B, where chamber A contains a solution of at least one drug and chamber B contains a pharmaceutically acceptable reconstitution solution of the solution of chamber A. 2. Kit according to claim 1, characterized in that the package Multi-chamber 1O is a package comprising a chamber A and a chamber B, wherein chamber A contains a solution of at least one drug and chamber B contains a pharmaceutically acceptable reconstitution solution of the solution of chamber A, so that the package has the means so that the solution of the chamber A and the solution of the chamber B can be mixed 15 within the same multi-chamber container due to total or partial breakage of the separation between chamber A and chamber B. 3. Kit according to claim 2, characterized in that the package Multi-camera is a bio-compatible plastic multi-camera bag, preferably a bio-compatible plastic double camera bag. 4. Kit according to any of the preceding claims, characterized in that the chamber A contains a solution, preferably aqueous, of at least one water-soluble drug. 5. Kit according to claim 4, characterized in that the low water soluble drug is an antifungal, wherein the antifungal is an azol derivative, preferably itraconazole, fluconazole, voriconazole, posaconazole, clotrimazole, ketoconazole, clotrimazole, econazole, saperconazole, ravuconazole, 30 isavuconazole, miconazole or thioconazole, more preferably itraconazole.

6.

Kit according to claim 5, characterized in that the solution in chamber A is an aqueous solution of the azol derivative, preferably

itraconazole, of concentration between about 1 mg / ml to about 30 mg / ml, preferably between about 5 mg / ml to about 20 mg / ml, more preferably of concentration about 1 O m g / mi.

7.

Kit according to any of claims 5 or 6, characterized in that the solution in chamber A comprises at least one inclusion complex of the azol-cyclodextrin derivative, preferably itraconazole-cyclodextrin.

8.

Kit according to claim 7, characterized in that the cyclodextrin is selected from the group of a, ~ and y-cyclodextrins optionally substituted by hydroxyethyl, hydroxypropyl, dihydroxypropyl, methyl hydroxyethyl, methyl hydroxypropyl, ethyl hydroxyethyl, ethyl hiproxypropyl groups, glucosil, maltosil, maltotriosil

or sulfoalkyl ether, preferably cyclodextrin is hydroxypropyl-cyclodextrin. 9. Kit according to any of claims 4 to 8, characterized in that the solution in chamber A further comprises a polymeric solubilizing agent or a mixture thereof, preferably a polyoxyethylene-polyoxypropylene copolymer, more preferably poloxamer 188. 1O. Kit according to any one of claims 4 to 9, characterized in that the solution in chamber A further comprises one or more solvents preferably selected from the group of ethanol, propylene glycol, oils and glycerin, more preferably propylene glycol.

eleven.

Kit according to any of claims 4 to 1 O characterized in that the solution in chamber A further comprises a pharmaceutically acceptable acid, preferably hydrochloric acid.

12.

Kit comprising a bio-compatible plastic double chamber bag comprising a chamber A and a chamber B, characterized in that chamber A contains between about 20 ml to about 25 ml of an aqueous solution of itraconazole of a

5 concentration approximately 1 O mg / ml and, preferably also hydroxypropyl- ~ -cyclodextrin, propylene glycol and hydrochloric acid, and chamber B contains between about 40 ml to about 50 ml of a NaCl solution at approximately 0.9% (by weight /volume). 1 O 13. Kit according to claim 12, characterized in that chamber A contains approximately 25 ml of the aqueous itraconazole solution and chamber B contains approximately 50 ml of the NaCI solution approximately 0.9% (by weight / volume). 14. Kit according to any of the preceding claims, further comprising a blister, preferably metallized, covering the multi-chamber container and, optionally, an extension path formed by a plastic tube with a two-way shut-off valve and an online filter. Use of the kit described in any of the preceding claims for the manufacture of a medicament.